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Innate immune response

Dans le document dendritic cells (Page 55-59)

Porcine reproductive and respiratory syndrome virus

1.5 Immune response against PRRSV

1.5.1 Innate immune response

1.5.1.1 Interference of TLR- and RIG-mediated signalling

In mammals, pathogens are sensed by cell membrane or intracellular pattern recognition receptors (PRRs). Host PRRs recognizing RNA viruses include Toll-like receptors (TLRs) and RIG -(retinoic acid inducible gene) I- like receptors (RLRs). TLRs that can sense viral RNA are TLR3 and TLR7. Both are endosomal TLRs respectively recognizing double and single stranded RNA (Bowie and Unterholzner, 2008; Sun et al., 2012; Thompson et al., 2011). RIG-I is an intracellular receptor for viral dsRNA (Bowie and Unterholzner, 2008; Gantier and Williams, 2007).

PRRSV mainly interferes with the TLR3 signalling pathway. Sang et al. (2008) and Miller et al. (2009) reported that activation of TLR3 by using chemical or exogenous dsRNA decreased the replication of PRRSV, while the same treatment on TIR (Toll/interleukin-1 receptor)-domain truncated TLR3 did not. In PRRSV-infected pigs, Miguel et al. (2010) and Liu et al.

(2009) detected the upregulation of TLR3 in discrete brain areas and the lymphoid tissues. In another study, Chaung et al. (2010) presented a contradictory result, showing that in vitro infection of PAMs and immature DC resulted in a transient inhibition of TLR3. Moreover, according to Kuzemtseva et al. (2014), TLR3 expression increased in PAM infected with PRRSV1 isolate 3262 but much less with isolate 3267, indicating the regulation of TLR3 may

There are also evidences that PRRSV may interact with RIG-I. Luo et al. (2008) and Song et al. (2010) showed that PRRSV nsp1α inactivated RIG-I in the IFNβ induction pathway. Huang et al. (2014) reported that nsp4 antagonized RIG-I-mediated NF-κB activation. And Sun et al.

(2016) showed nsp11 interferes with transcription and translation of two critical factors, MAVS (mitochondrial antiviral-signalling protein) and RIG-I, in the RLR-mediated pathway.

1.5.1.2 Inhibition of type I interferons (IFN)

Production of type I IFNs represents the most effective innate antiviral immune response, limiting viral replication and spread (Baum and Garcia-Sastre, 2010). PRRSV appears to inhibit the production of type I IFN in PAM and in myeloid DC. In an early experiment, Albina et al. (1998a) showed that PAM exposed to PRRSV did not produce any detectable amount of IFN-α. When PAM were further superinfected with the gastroenteritis transmissible virus -a potent inducer of type I IFN- PRRSV abolished IFN-α production as well.

Buddaert et al. (1998) also studied the in vitro and in vivo expression of IFN-α after PRRSV infection. Their results indicated that induction of IFN-α by PRRSV in vitro was very low but seemed not to be affected in vivo, since the cytokine could be detected in the lung of infected animals. In any case, treatment of PAM with recombinant type I IFN significantly blocked PRRSV replication. Royaee et al. (2004) provided evidence that exogenous addition of IFN-α during PRRSV vaccination increased the Th1 response. This observation partly explains the poor cell-mediated response generated after vaccination.

The inhibition of IFN depends to some extent on the strains as evidenced by Lee et al. (2004).

Those authors examined IFN-α responses of macrophages and observed that different isolates -and even some plaque-purified variants- have different sensitivities to IFN-α and induced

When plasmacytoid DC (pDC) were examined, results were more controversial. While Calzada-Nova et al. (2011) indicated that PRRSV2 inhibited the release of type I IFN in pDC regardless of the virus viability, Baumann et al. (2013) showed that all examined PRRSV1 and most PRRSV2 strains had no or very weak suppression of IFN-α in enriched pDC. Most likely, only some PRRSV isolates had the capability of inhibiting pDC functionality, among them were several highly pathogenic PRRSV2 strains (Baumann et al., 2013). The effects of PRRSV on different types of DC are revised in depth in another section of this introduction.

Regarding the possible mechanisms involved in the inhibition of type I IFNs, Miller and Fox (2004) showed that, blocking of the transcription in MARC-145 cells, was the most likely cause. However, many other studies suggested a post-transcriptional regulatory mechanism by showing abundant IFNα/β gene transcripts but negligible amounts of the cytokine protein in PRRSV-infected macrophages, MoDC and, DC collected from lungs (Lee et al., 2004; Loving et al., 2007; Zhang et al., 2012).

Until now, five PRRSV proteins have been identified as IFN antagonists, including four non-structural proteins: nsp1, nsp2, nsp4 and nsp11, and the N protein. Among these antagonists, nsp1 is considered the most potent inhibitor. Nsp1 contains two sub-units designated as nsp1α and nsp1β (Kappes and Faaberg, 2015). Non-structural protein 1β inhibits dsRNA-mediated IRF3 phosphorylation and nuclear translocation, and inhibits STAT1 translocation in JAK–

STAT signalling pathway, resulting in the inhibition of both IFN synthesis and signalling (Chen et al., 2010; Song et al., 2010).

Non-structural protein 2, the biggest nsp of the virus, contains a cysteine protease domain (belonging to the ovarian tumor protease family, OTU) that possesses ubiquitin-deconjugating activity. In vitro, PRRSV infected cells suffer a blocking of IRF3 phosphorylation and nuclear

translocation (Li et al., 2010), and the inhibition of NF-κB activation by the OTU domain (Sun et al., 2010).

For nsp4, it has been shown that this protein suppresses IFNβ transcription by blocking NF-κB (Huang et al., 2014) and, nsp11 inhibits Poly(I:C)-induced IFN𝛽 production through the endoribonuclease activity (Shi et al., 2011). N protein, similarly to nsp1, localizes in both cytoplasm and nucleus. Its ability to suppress type I IFN induction has been verified, but whether the nuclear translocation is involved remains unknown (Huang et al., 2015).

1.5.1.3 TNF-α, IL-10 and other cytokines

Tumor necrosis factor-α (TNF-α) is one of the central pro-inflammatory cytokines. It can be produced as a part of the innate immunity by macrophages, DC and NK cells, and in the development of acquired responses by T-lymphocytes.

The role of TNF-α in PRRSV infection has been thoroughly studied. Early works reported contradictory results that some authors found an inhibition of this cytokine (Lopez-Fuertes et al., 2000; Thanawongnuwech et al., 2001; Van Reeth et al., 1999), while others observed an induction (Ait-Ali et al., 2007; Chen et al., 2010; Choi et al., 2002). Darwich et al. (2011) clarified this issue by showing that the induction of TNF-α was strain-dependent. Chen et al.

(Chen et al., 2010) indicated that the production of TNF-α in PRRSV-stimulated (or infected) cells may result from the response to a variable part of nsp2.

IL-1 and IL-8 are also considered as important pro-inflammatory cytokines in PRRS and, in general, have been related to the development of inflammatory responses during the infection, for example, development of interstitial pneumonia (Aasted et al., 2002; Labarque et al., 2003;

Thanawongnuwech et al., 2001; Van Gucht et al., 2003; Van Reeth et al., 1999).

IL-10, however, is a crucial immune-regulatory cytokine that can inhibit the production of inflammatory cytokines and counteract adaptive immunity. A variety of cells, including monocytes/macrophages, DC, T and B cells, can be induced to produce IL-10. Several studies (Diaz et al., 2005; Diaz et al., 2006; Peng et al., 2009; Silva-Campa et al., 2009; Suradhat and Thanawongnuwech, 2003; Suradhat et al., 2003) indicated that in vitro infection with PRRSV resulted in an increase of IL-10 levels. However, other studies suggested a minor role of this cytokine (Silva-Campa et al., 2010; Subramaniam et al., 2011). Later, this discrepancy was explained by the observation that different PRRSV isolates showed different profiles in IL-10 induction (Darwich et al., 2011; Silva-Campa et al., 2010).

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